Efficacy of invasive laser acupuncture in treating chronic non-specific low back pain: A randomized controlled trial

This study aimed to provide preliminary evidence for the efficacy of invasive laser acupuncture (ILA) for chronic non-specific low back pain (CNLBP). This was a single-center, randomized, patient and assessor-blinded, placebo-controlled, parallel-arm, clinical trial with a 1:1:1 allocation ratio that included a full analysis set. Forty-five participants with CNLBP were randomly assigned to the control group (sham laser), 650 group (650 nm-wavelength ILA), or 830 group (830 nm-wavelength ILA) (n = 15/group). All participants received ILA for 10 min, followed by electroacupuncture for 10 min on the same day. The treatment was performed once per day, twice per week for 4 weeks at bilateral BL23, BL24, BL25, and GB30. The primary outcome was the among-group difference of changes in the visual analog scale (VAS) scores at intervention endpoint (week 4). The secondary outcomes were the among-group difference of changes in VAS at 4 weeks after intervention completion (week 8), those in the Korean version of the Oswestry Disability Index (ODI) and the European Quality of Life Five-Dimension- Five-Level (EQ-5D-5L) at intervention endpoint (week 4) and 4 weeks after intervention completion (week 8). The VAS scores of the 650 group decreased significantly compared with those of the control group (p = 0.047; week 4 vs. week 0). The ODI scores of the 650 group (p = 0.018, week 4 vs. week 0; p = 0.006, week 8 vs. week 0) and 830 group (p = 0.014, week 4 vs. week 0) decreased significantly compared with those of the control group. There was no adverse event related to ILA and no significant difference in changes in vital signs among the three groups. The 650 group showed significant improvements in pain intensity and functional disability. The 830 group showed significant improvements in functional disability. Therefore, ILA therapy at 650 nm and 830 nm wavelengths can be used to treat CNLBP.

subgroup of LLLT, it is considered to be a separate form of treat ment. Instead of using the direct effect of light 23 on tissues to initiate a physiological response, the selection of points is based on a diagnostic and therapeutic 24 paradigm defined by acupuncture theories [13,15]. Different wavelengths, energy doses, and acupoints affect the 25 effects of laser acupuncture [16][17][18]. 26 A meta-analysis of randomized controlled trials (RCTs) of LLLT (including LA) for CLBP reported a moderate 27 quality of evidence (GRADE) to support a clinically important benefit of LLLT for CLBP in the short term, 28 which was only seen after higher laser-dose interventions and in participants with a shorter duration of back pain 29 [14]. However, a couple of RCTs reported that noninvasive LA did not show significant effects as compared 30 with sham lasers in patients with LBP [13,19]. 31 Noninvasive LA is applied to the skin and can be used as an alternative to needles through the use of laser-32 emitting devices. Invasive LA (ILA) involves the simu ltaneous application of invasive acupuncture treatment at 33 acupoints and focused laser irradiat ion using a laser machine connected to an acupuncture needle consisting of 34 an optical fiber-coupled laser diode. Previous studies showed that ILA co mbined with other treat ments has 35 significant effects on neuropathic pain and rheumatoid arthritis in rat models [20,21]. However, relatively little 36 evidence was obtained from clin ical trials regarding the use of ILA for CLBP, especially rigorous randomized 37 controlled clinical trials reporting on the efficacy of ILA. Therefo re, we intend to obtain basic data regarding the 38 efficacy and safety of ILA for CLBP by comparing the effects of different wavelengths of ILA. This study was a prospective, patient-blinded, parallel-arm, single-center (DongShin Un iversity Gwangju 55 Korean Medicine Hospital, Republic of Korea), p ilot randomized controlled clin ical trial with a 1:1:1 allocation 56 ratio. A total of 45 participants who met the inclusion criteria will be rando mly allocated to the control, 650-n m 57 ILA (650 ILA ), or 830-n m ILA (830 ILA ) group (n = 15 in each group). Part icipants in the control group will 58 receive sham ILA for 10 min and real electroacupuncture (EA) for 10 min, while those in the 650 and 830 ILA 59 groups will receive real ILA (i.e., 650 ILA g roup, 650-n m wavelength; 830 ILA g roup, 830-n m wavelength) and 60 real EA both for 10 min . Participants will receive treat ment once/day, twice/ week for 4 weeks, at b ilateral 61 Shenshu (BL23), Qihaishu (BL24), Dachangshu (BL25), and Huantiao (GB30). 62 The primary outcome will be imp rovements in pain intensity assessed using the visual analogue scale (VA S). 63 The secondary outcome measures will include changes in scores in the Korean version of the Oswestry 64 Disability Index (ODI) and the European Quality of Life Five Dimension Five Level scale (EQ-5D-5L). All 65 scale scores will be recorded at baseline (before intervention), 4 weeks after the first intervention (i.e., at the end 66 of the intervention), and 4 weeks after completion of the intervention. 67 This study protocol comp lies with the principles of the Declaration of Helsin ki and Korean Good Clin ical 68

Participant recruitment 77
Participants will be recruited at the DongShin University Gwangju Korean Medicine Hospital, Republic of 78 Korea. The study will be advertised through local newspapers, the Internet, and posters in communities and 79 hospitals. Interested individuals will receive instructions for clinical trial part icipation through phone calls or 80 visits to our hospital. When interested individuals visit the clinical research center at DongShin Un iversity 81 Gwangju Korean Medicine Hospital, they will receive an explanation about the study fro m the clinical research 82 coordinator (CRC) and will be asked to voluntarily sign an informed consent form prior to participation. 83 To facilitate participation in the study, the CRC will ad just the treatment and evaluation schedules of each 84 individual participant. Every time the participants visit, the CRC will exp lain the schedule for the fo llo wing visit 85 and will remind the participant of the schedule by phone on the day before the appointment. The CRC will 86 continuously monitor the medical condition of the enrolled participants to ensure their adherence to the 87 intervention protocols. 88 89

Inclusion criteria 90
Participants who meet all of the follo wing criteria will be included in this trial: 1) aged between 19 and 70 91 years; 2) has CLBP lasting for at least the previous 3 months; 3) scored ≥40 points on a 100-mm VA S for pain 92 at the time of screening; 4) has adequate level of Korean language proficiency for the reliable co mplet ion of all 93 study assessments; and 5) voluntarily provides informed consent. 94

Exclusion criteria 95
The exclusion criteria are as follows: 1) radicu lar pain or progressive neurological deficits; 2) diagnosis of a 96 serious spinal pathology (cancer, recent vertebral fracture, spinal infection, or inflammatory spondylitis); 3) 97 presence of a serious chronic disease (cancer, severe cardiovascular, cerebrovascular, liver, kidney disease, or 98 diabetic neuropathy); 4) history of treatment for alcohol/drug dependency or mental illness (schizophrenia, 99 dementia, or epilepsy) in the 6 months preceding enrollment; 5) LBP not caused by a spinal or soft tissue 100 disease (trauma, anky losing spondylitis, fib ro myalgia, rheumatoid arthritis, or gout); 6) presence of 101 contradictions for LA or EA, such as blood clotting abnormalit ies (hemophilia), severe skin d isease in the 102 lu mbar region, presence of metallic devices in the lu mbar spine, or p resence of electronic med ical devices 103 (pacemaker); 7) previous lu mbar spinal surgery within a year or scheduled procedures during the study; 8) 104 pregnancy or planning to become pregnant; and 9) concurrent participation in other clinical trials.

Dropout criteria 107
Participants will be dropped from the trial under the follo wing conditions: 1) <75% co mpliance with the 108 protocol procedures (participating in <6 of the 8 scheduled treatment sessions ); 2) occurrence of a serious 109 adverse event (SAE); 3) reluctance to continue the trial; 4) incomp lete data that could influence the trial; 5) 110 large erro rs in protocol or significant deviations in implementation; or 6) if the principal investigator (PI) or 111 institutional review board (IRB) decides to terminate their participation in the trial. After the acquisition of written info rmed consent, the practitioners who will be performing the intervention will 121 conduct a screening interview. Then, the assessor will perform baseline measurements for participants who meet 122 the inclusion criteria. The 45 enrolled participants will be immediately assigned serial numbers generated using 123 the SPSS version 21 software (IBM Corp., Armon k, NY, USA) and rando mly allocated to 1 of the 3 study 124 groups (n = 15 per group). The serial nu mber codes will be inserted in opaque envelopes that will be sealed and 125 stored in a double-locked cabinet; these will be opened by the PI or practit ioners who will perform the 126 intervention in the presence of the patient and a guardian. 127 128

Implementati on 129
The CRC will generate the allocation sequence, enroll participants, and assign participants to the interventions. Owing to the nature of LA treat ment, a double-blind study design cannot be adopted. Therefore, we will adopt 133 a patient-blinded trial procedure using sham LA. During the course of this clinical trial, the assessor will have 7 no contact with the participants other than at the time of assessment. Furthermo re, unblinding will not be 135 permitted under any circu mstances. However, if an SAE occurs, unblinding will be permitted after an ag reement 136 between all the researchers involved. To prevent selection, performance, and attrit ion biases due to the 137 unblinded participants and practitioners, this study will only involve individuals without conflicts of interest or 138 preconceived positions. All the practitioners who will perform the interventions will receive training in clinical 139 trials before participation. A statistician not involved in the design or execution of the clinical trial will analyze 140 the final data. 141 142

Interventions 143
The treatment will be admin istered by Korean medical doctors with 6 years of formal university training in 144 Korean med icine and a license to ad min ister treat ments. To ensure strict adherence to the study protocol, the 145 practitioners who will perform the interventions will undergo training together and use the same techniques 146 (Table 1). 147

149
ILA and EA will be performed with a med ical device co mposed of a combination of a sterile, stainless steel, will not be used. Participants in the control group will receive sham ILA fo r 10 min and real EA for 10 min, 157 while those in the 650 and 830 ILA groups will receive real ILA (650 ILA g roup, 650-n m wavelength; 830 ILA 158 group, 830-n m wavelength) and real EA both for 10 min. Participants will receive treat ment once/day, 159 twice/week for 4 weeks. The laser parameters will be as follows: pulse mode, pu lse-type wave; output power, 20 160 mW ; frequency, 50 Hz; and irradiated area, 0.15 × 0.15 mm 2 . EA will be applied with a biphasic waveform 161 current, which is a co mpressional wave that co mb ines an interrupted wave and a continuous wave, in triangular 162 form, at a frequency of 50 Hz [27]. On the basis of the previous RCTs to investigate the efficacy of LLLT on 163 CLBP [13, 19], the control group will undergo the same procedures as the ILA group, but the laser will not be 164 turned on. The acoustic functions of the equipment will be preserved to ensure blinding. No significant 165 differences in observation, feeling, or sound should be found between the 3 groups during the procedure. Hence, 166 all participants will be blinded to the group selection. 167 All participants should comply with the protocol procedures such as the allocated intervention and treatment 168 schedules. However, the treatment schedule may be changed according to the judgment of the PI or the request 169 of the participant. 170 During the clinical trial period, all part icipants will be allo wed to continue the routine management regimens, 171 existing medicat ions (e.g., those for hypertension, diabetes, or hyperlipidemia), and med ications for maintain ing 172 and improving their health status. However, they will not be permitted to engage in other treatments 173 (pharmacological treat ments, physical therapy, or CAM therapies) to ameliorate their CLBP sympto ms. All 174 med ical devices will be inspected by the investigators, who will record the results of checkups in the 175 management register.

Outcome measurements 181
In accordance with the study objective, improvements in pain intensity assessed using the VAS will be 182 considered the primary outcome, and the secondary outcomes will be the changes in ODI and EQ-5D-5L. VA S, 183 ODI, and EQ-5D-5L scores will be recorded before intervention, at the end of intervention, and 4 weeks after 184 the completion of the intervention. The primary end point will be the VAS score recorded at the end of the 185

intervention. 186
The VAS is a 10-cm-long straight line marked at each end with the anchor labels "no pain " and "pain as bad as 187 it could be" [28]. Participants will be asked to mark a point representing the severity of their pain. Scores are 188 recorded in millimeters, and the total score ranges from 0 to 100 mm [29]. The validated Korean version of the EQ-5D includes generic questions about personal health-related quality of 195 life and 5 dimensions pertaining to mobility, self-care, usual activit ies, pain/discomfort, and an xiety/depression. 196 Each d imension has 3 response categories, namely "none," "some," and "extreme/unable to," with lo wer scores 197 indicating a better state of health [32,33]. The EQ-5D-5L is a new version of the EQ-5D that includes 5 levels of 198 severity (none, slight, moderate, severe, and extreme/unable) for each of the 5 EQ-5D dimensions [34]. 199 200

Incidence of AEs 201
AEs are undesirable and unintentional signs, symptoms, or diseases that appear during or after treat ment in a 202 clin ical trial. Part icipants in this study will be required to voluntarily report any A Es. A ll A Es that occur during 203 the trial will be documented. A Es that could occur in this study include skin irritation, b leeding, local hemato ma, 204 pallor, sweating o r d izziness, fainting during acupuncture treatment, continuous severe pain fo r >1 hour after 205 acupuncture treatment, objective worsening of existing symptoms , and undesirable and unintentional signs, 206 symptoms, or d iseases. The CRC will record all A Es in detail, including the time and date of occurrence, degree 207 of severity, any measures related to the treatment of the AE, and any potential causal relationships between the 208 treatment and the AE. All A Es will also be reported to the PI and relevant IRB. In case of SA Es, defined as AEs 209 causing severe disability or malfunction, appropriate measures will be taken, and the incident will be 210 immed iately reported to the PI and relevant IRB. In cases in which an A E occurs because of the clinical trial, 211 participants will notify the CRC and PI and will be compensated. 212

Quality assurance 214
This protocol has been reviewed and rev ised several times by experts on acupuncture, orthopedics, statistics, 215 and methodology. Before the trial, all the researchers will be requested to attend a series of training sessions , 216 which will ensure that the personnel involved fully understand the trial protocol and standard operating 217 procedures (SOPs) of the study. The data monitoring committee (DMC) will co mprise the PI, CRC, and a 218 researcher who will not be involved in the data collection aspect of this study. The DMC, wh ich is independent 219 fro m the sponsor and free fro m co mpeting interests, will manage the data to ensure data validity. This study will 220 be monitored by a clinical research associate (CRA), who will check all documents related to this study, 221 including the case report forms (CRFs) and SOPs, and ensure that this clinical trial is conducted in accordance 222 with the prescribed protocols and SOPs. Monitoring will be performed by an independent CRA, who will not be 223 involved in any other aspect of the trial. In the event that the protocol described herein is revised, the revisions 224 We had no preliminary study or adequate previous studies upon which to base sample size estimates. Therefore, 229 we adopted a pilot study design. The appropriate sample size for two-or three -arm pilot studies is >12 [35,36]. 230 Considering a dropout rate of 20%, we assigned 15 participants to each group (45 in total). 231 As our study is a pilot study, the sample size will not be sufficient for determin ing the efficacy of ILA for 232 CLBP. Our study provides preliminary evidence for the efficacy and safety of ILA for CLBP. 233 234

Statistical analysis 235
A statistician not involved in data collection will analy ze the final data. We will perform a full analysis set (FA 236 group) to assess the efficacy and a supplementary per-protocol analysis (PP group). We will co mpare the results 237 of the statistical analyses between the FA and PP groups, and confirm any statistically significant differences 238 between the groups. If a significant d ifference exists between the PP and FA groups, the cause will be reviewed 239 and reflected in the efficacy assessment. Missing values will be obtained using the "last observation carried 240 forward" method. Interim analyses will not be performed. All statistical analyses will be perfo rmed using the 241 SPSS version 21 software. 242 Baseline characteristics will be described and co mpared between the groups. Continuous data will be presented 243 as means and standard deviations and compared using the independent t test or Mann-Whitney U test 244 (nonparametric test). Categorical data will be presented as frequencies and percentages and compared using the 245 chi-square or Fisher exact test. 246 Within each group, changes in VAS, ODI, and EQ-5D-5L scores at 4 weeks (the end of intervention) and 8 247 weeks (4 weeks after the end of intervention) after the start of intervention, relative to the baseline score, will be 248 analyzed using a paired t test or Wilcoxon signed rank test (nonparametric test). Trends over time and time-by-249 treatment interactions will be explo red using repeated-measure analysis of variance. The degrees of changes in 250 the VAS, ODI, and EQ-5D-5L scores at each time point between the groups will be evaluated using the 251 independent t test or Mann-Whitney U test (nonparametric test). Subanalyses will be performed according to 252 participant age. All reported p values will be t wo-sided, with 95% confidence intervals. A p value < 0.05 will be 13 considered statistically significant. 254 A safety assessment will be performed for all A Es that will occur during the study period. The incidence of 255 AEs and SAEs will be summarized by group and analyzed using the chi-square or Fisher exact test. 256 257

Confidentiality and data management 258
All identification records of the participants will be kept confidential. When the results of the study are 259 published, the identification records will be accessible under IRB approval. All docu ments related to the trial, 260 including CRFs, will be recorded and labeled with participant identification codes and will not reveal the name 261 of the participants. The serial nu mber codes will be stored in sealed, opaque envelopes and kept in a double-262 locked cabinet. All part icipant data will be recorded in Excel files by the CRC. A ll data will be checked by the 263 CRC and rechecked by a researcher, both of who m will not be included in the data co llection phase of the study 264 to ensure the reliab ility of the data. Continuous data will be coded as data values, and categorical data will be 265 coded as number sets for each item by a statistician not involved in the data collection phase of this clinical trial. 266 The data entry and coding will be double-checked. Electronic data will be stored on a password-protected 267 computer. Anyone who is not approved by the IRB will not be able to access the data. In addition, raw data 268 (CRFs) will be stored in a cab inet until the end of the study. Written informed consent for the publication of the 269 individual details and accompanying images will be obtained from the participants.